A major focus of the field of aging and dementia is the investigation of the causes of cognitive impairment. Various conditions, such as dementias (e.g., Alzheimer's Disease, Lewy body dementia, vascular dementia, and HIV associated dementia), neurodegenerative diseases (e.g., Huntington's Disease, Parkinson's Disease, amyotrophic lateral sclerosis), neurological disorders (e.g., schizophrenia, depression), and age-related conditions (e.g., Mild Cognitive Impairment, Age-Related Cognitive Decline), are associated with cognitive impairment. As the understanding of cognitive impairment increases, so does the need to develop sensitive methods to both detect and to treat such impairment.
Accumulating evidence suggests that there is a neurogenetic component to cognitive impairment. For example, changes in the mammalian brain appear to parallel alterations in distinct learning and memory processes. See, e.g., Albert, Philos. Trans. R. Soc. Lond. B. Biol. Sci. 352(1362):1703-09 (1997). In particular, alterations in the hippocampal formation are among the most prominent and consistent features observed in age-related cognitive impairment. Gallagher, Philos. Trans. R. Soc. Lond. B. Biol. Sci. 352(1362):1711-7 (1997). Changes in the aged hippocampus also parallel, to some extent, the hippocampal changes observed in other conditions associated with cognitive impairment, such as Alzheimer's Disease. Whitehouse et al., Science. 215(4537):1237-39 (1982); Bartus et al., Science. 17(4558):408-14 (1982); Rapp and Heindel, Curr. Opin. Neurol. 7(4):294-8 (1994). Thus, the effects of aging on hippocampal function may be related at some level to disease processes in progressive neurodegenerative illnesses.
The mammalian hippocampus is a structure that contains distinct populations of neurons organized into separate anatomical subregions. These subregions include, for example, the dentate gyrus (DG) and the Cornu Ammonis (CA) subfields CA1 and CA3. Each hippocampal subregion is characterized by a unique molecular profile. Lein et al. J. Neurosci. 24(15):3879-89 (2004). These different profiles may account for the differential vulnerability of these regions to various mechanisms of cognitive impairment. See, e.g., Small et al. Proc. Natl. Acad. Sci. USA. 101(18):7181-6 (2004).
Considerable research has examined the correlation between changes in cognitive function and neuronal changes in specific hippocampal subregions. This research suggests that the specific nature and extent of hippocampal damage parallels in some cases the degree and type of cognitive impairment. See, Jarrard, Behav. Neural. Biol. 60(1):9-26 (1993). For example, synaptic alterations specific to the CA1 region correlate with age-related impairments in cellular responsiveness to glutamate receptor stimulation. Barnes et al., Hippocampus. 2(4):457-68 (1992). Likewise, individual differences in spatial learning ability correlate with expression levels of NR1, an N-methyl-D-Aspartate (NMDA) receptor subunit, selectively in CA3 neurons. Adams et al., J. Comp. Neurol. 432(2):230-43 (2001). And, levels of synaptic markers in the DG correlate with individual levels of cognitive impairment in spatial learning capacity among aged rats. Smith et al., J. Neurosci. 20(17):6587-93 (2000). These correlations do not, however, establish that the neuronal changes cause the observed functional changes. Just as, importantly, changes in the hippocampus and cognitive function do not occur solely as a result of aging per se. Thus, comparisons based on chronological age alone often fail to capture the hippocampal changes that correlate with individual levels of cognitive impairment.
Although some impairment in both cognitive function and hippocampal integrity may be a normal consequence of healthy aging, a significant population of elderly adults experiences a decline in cognitive ability that exceeds normal development. Thus, the effect of aging itself on cognition, in the absence of dementia or disease, is important for defining the boundary between illness and normal aging.
Heterogeneous patterns of progressive cognitive impairment are characteristic of mammalian test populations, e.g., aged humans and aged laboratory animals. The increasing preponderance of ‘individual differences’ in cognitive impairment has been used to characterize normal mammalian aging itself. Baxter and Gallagher, Neurobiol. Aging. 17(3):491-95 (1996).
There is, therefore, a need to elucidate the molecular basis of and to treat cognitive impairment, both in aging and in disease. There is also a need to understand the neurogenetic components of cognitive impairment and to develop a range of treatment options for individuals with varying levels of impaired cognition.
The examination of changes in expressed gene products in the hippocampus of the mammalian brain, as described in this invention, may serve to elucidate the genetic or molecular basis of cognitive impairment. Moreover, the examination of changes in expressed gene products in the aged hippocampus may serve to elucidate the genetic or molecular basis of cognitive impairment in aging. The identification of genes, or a plurality of genes, that are associated with cognitive impairment, and particularly that are associated with age-related cognitive impairment, would also allow the identification of compounds for treating such impairment.